COVID-19 Virtual Symposium #25

The twenty-fifth Columbia COVID-19 virtual symposium

By
VP&S Office for Research
December 02, 2020

Today was the twenty-fifth Columbia COVID-19 Virtual Symposium.

Presentation Summaries and Video Recordings

Written summaries were kindly provided by the Presenters or the Columbia Researchers Against COVID-19 (CRAC) Team.

If you are having trouble viewing the embedded videos, try refreshing the page. If that doesn't work, visit the Herbert Irving Comprehensive Cancer Center's YouTube page

Intro: Stephen Goff, PhD, Andrea Califano, PhD, Eric Greene, PhD and Andy Marks, MD

Title: COVID-19 Resources: General availability of RNASeq and Exome Profiles from NYP
COVID-19 patients to support Columbia Research on SARS-CoV-2

Summary: Dr. Califano shared resources and data availability of COVID-19 patient sequencing data. To access this data please submit an application to the Sample and Data Access Committee: https://cumc.co1.qualtrics.com/jfe/form/SV_7833FlNRraroUxn If and when approved, CUB staff will provide instructions for accessing RNAseq data. Furthermore, instructions for linking your IRB or submitting a TRAC request for clinical data can be found on their website:  https://www.ps.columbia.edu/research/core-and-shared-facilities/core-facilities-category/columbia-university-biobank

Kizzmekia Corbett, PhD, Senior Research Fellow and Scientific Lead Coronavirus Vaccines & Immunopathogenesis Team Viral Pathogenesis Laboratory Vaccine Research Center National Institutes of Allergy and Infectious Diseases National Institutes of Health, United States

Title: SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

Summary: Dr. Corbett’s work is focused on coronaviruses, especially those which have pandemic potential in humans. Prior to the emergence of SARS-CoV-2, their group worked on a proof-of-concept study of their prototype pathogen approach for pandemic preparedness. They used the MERS virus in this study with the idea that this “plug and play” approach could provide fast, reliable and universal vaccine solutions. In this case, the viral spike protein, which is crucial for viral entry into host cells, was used as the antigen. By introducing a two proline mutation into the spike protein, the protein is stabilized and elicits an improved neutralizing antibody response in comparison to the native conformation. In collaboration, Dr. Corbett’s group used Moderna’s mRNA platform to deliver the spike protein antigen and were able to show only 37 days following the release of the viral sequence from China that the prototype vaccine showed immunogenicity in mice. From there, Phase I clinical trials were started 66 days from the sequence release. As of today, the Phase III clinical trials for mRNA-1273 from Moderna have been completed and shown to stimulate neutralizing antibody responses in young and old adult patient cohorts. These studies demonstrate the rapidness with which this vaccine design can be developed and provide platforms by which future vaccines can be implemented rapidly and safely.

Kizzmekia Corbett's presentation

Walther Mothes, PhD, Professor of Microbial Pathogenesis Co-Leader, Cancer Microbiology Yale School of Medicine, United States

Title: Real-time conformational dynamics of SARS-CoV-2 spikes on virus particles

Summary: Dr. Mothes group has been working on defining the real-time dynamics of the SARS-CoV-2 spike protein which has become a promising vaccine target. Spike protein exists in multiple conformations and is dynamic. Using single-molecular FRET, Dr. Mothes group was able to observe these dynamics in real-time. Interestingly, they also found that antibodies and patient’s plasma stabilized the ground state confirmation of the spike protein, which mimicked the conformation that ACE2 causes when it binds to the spike protein. They also found that some antibodies were also able to allosterically block the activation of the spike protein, locking the spike protein into the down conformation. In the future, these studies will be paired with cryoEM to gain a better understanding of the structural rearrangements of the spike protein.

Walther Mothes's presentation

Bruno Canard, PhD, Senior Researcher Viral Replication: Structure, Mechanisms, and Drug Design CNRS-Aix Marseille University, France

Title: The outstanding SARS-CoV RNA synthesis machinery

Summary: Dr. Canard’s group has been dedicated to learning more about viral replication mechanisms and in particular the cellular machinery used by coronaviruses for RNA replication. Coronaviruses have very large RNA genomes and Dr. Canard characterized Orb1a/1b as important for replication and transcription. Most recently, they have defined nsp12 (RdRp) as the main RNA-dependent RNA polymerase. They found that RdRp is very conserved between SARS-1 and SARS-2 with only one motif not conserved. Most of the changes are in external loops and suggests that most inhibitors of RNA polymerization should work for both viruses. They also found that Nsp12 requires Nsp7 and Nsp8 to form a replication complex and have extremely rapid polymerization. SARS-2 has almost ten times faster polymerization than most viruses at the expense of low fidelity. Dr. Canard’s group then used different nucleoside and nucleotide analogs to block RNA polymerization such as remdesivir, ribavirin, sofosbuvir and favipiravir as potential therapeutic options for coronavirus infection.

Bruno Canard's presentation

Rory de Vries, PhD, Assistant Professor Department of Viroscience Erasmus Medical Center, Netherlands

Title: Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets

Summary: Besides vaccines, other prophylactic options such as nasal sprays may become critical for breaking the chain of transmission in the SARS-CoV-2 pandemic. Dr. de Vires presented in vitro and in vivo studies showing that their fusion inhibitory peptide was capable of blocking viral entry into the host cell by preventing fusion of the spike protein. Their fusion inhibitory peptide prevents structural rearrangements of the spike protein which blocks viral particle fusion and entry. They found that lipid tagging and dimerizing this inhibitory peptide improved efficacy by preventing fusion by the spike protein. They also noted that this peptide was effective against different variants of the spike protein as well as the MERS virus. To confirm that this inhibitory peptide could also work in vivo they used ferrets as an animal model as ferrets have proven to be a good model for viral transmission, though not for disease. They found that pre-treatment with the peptide blocked viral entry and thereby infection in animals that received the fusion inhibitory peptide. Thus, the peptide blocked contact transmission in the ferrets and no infection or viral fusion was observed in those treated with the fusion inhibitory peptide. These data are promising for translation into humans whereby a nasal spray with the fusion inhibitory peptide could be taken prophylactically before traveling or attending crowded events such as concerts or sports.

Rob E. Schwartz, MD, PhD, Assistant Professor Physiology, Biophysics & Systems Biology Weill Cornell Medicine, United States

Title: Development of Stem Cell/Organoids Models for COVID-19 Disease Modeling

Summary: As we learn more about COVID-19 it has become apparent that the SARS-CoV-2 virus has effects on not only the lung but on many organ systems. Dr. Schwartz’s group sought to characterize SARS-CoV-2 infection using organoid models. His group used iPS derived cells to generate organoids for multiple organ systems including the lung, liver, colon and pancreas. They found that lung, liver, colon, heart and pancreas organoids were the most permissive to viral entry and replication and surprisingly found that pancreatic islet cells were particular permissive to infection with SARS-CoV-2. Specifically, beta cells which produce insulin, showed a dedifferentiation phenotype. Furthermore, chemical screens on lung and colon organoids uncover imatinib, mycophenolic acid (MPA), quinacrine dihydrochloride (QNHC) as possible therapeutic options, Indeed, MPA is currently being evaluated in clinical trials.

Rob E. Schwartz's presentation

Bronwyn MacInnis, PhD, Director of Pathogen Genomic Surveillance Infectious Disease and Microbiome Program Broad Institute, United States

Title: Phylogenetic analysis of SARS-CoV-2 in the Boston area: disparate consequences of importations and superspreading events

Summary: Dr. MacInnis’s work is focused on defining the transmission of SARS-CoV-2. Particularly, this work was focused on transmission in Massachusetts with data biased towards cases in Boston in 800 SARS-CoV-2 genomes from March-May. They found that in the first wave of the outbreak in March and April that transmission was associated with congregate living settings and high-risk communities. They also noted that the virus was introduced from Europe and that recurrent introduction of the virus was prevalent in the Northeastern United States. This was most likely due to lack of enforcement of border closures and quarantines. Of note, most cases did not result in onward transmission, but a small number of super-spreaders cause much of the transmission and disease burden. For example, an international business conference in late February was associated with one super-spreader case that seeded 30% of all cases in Massachusetts and lead to transmission across the United States and the world. Their work underscores the importance of testing and contact tracing to intervene and break the chain of transmission in these super-spreading events.

Bronwyn MacInnis's presentation

Thomas Lane, PhD, Professor Department of Neurobiology & Behavior University of California, Irvine, United States

Title: Exploring the roles of microglia in host defense and disease in response to SARS-CoV-2 infection of the CNS

Summary: SARS-CoV-2 infection in particular, compared to SARS-CoV-1 and MERS, results in neurological symptoms in COVID-19 patients. Dr. Lane’s group uses mouse models and single-cell sequencing studies to define how the microglia are affected during viral infection. In mice infected with mouse coronavirus the ablation of microglia results in increased mortality and viral load in the brain and spinal cord. Notably, the overall immunological landscape does not change but B cells do increase with microglial ablation and there is muted activation of CD4 T cells and decreased MHC Class II in macrophages. It was also noted that demyelination was increased in microglial ablated mice as well as a lack of remyelination. In SARS-CoV-2 infection, the lack of microglia did not result in increased clinical presentation but slightly more severe disease with a higher viral load in the brain. They also found that neurons were the primary cellular reservoir for SARS-CoV-2 in the brain. A large amount of the virus was present in the brain stem but differences in demyelination were not observed within the spinal cords. Future studies will interrogate the immune response in the brains of so called COVID-19 “long-haulers”.

Thomas Lane's presentation

Andrea Califano, PhD - Clyde and Helen Wu Professor of Chemical and Systems Biology Chair, Department of Systems Biology Director, JP Sulzberger Columbia Genome Center, Columbia University                               

Title: COVID-19 Resources: General availability of RNASeq and Exome Profiles from NYP COVID-19 patients to support Columbia Research on SARS-CoV-2

Summary: Dr. Califano shared resources and data availability of COVID-19 patient sequencing data. To access this data please submit an application to the Sample and Data Access Committee: https://cumc.co1.qualtrics.com/jfe/form/SV_7833FlNRraroUxn If and when approved, CUB staff will provide instructions for accessing RNAseq data. Furthermore, instructions for linking your IRB or submitting a TRAC request for clinical data can be found on their website: https://www.ps.columbia.edu/research/core-and-shared-facilities/core-facilities-category/columbia-university-biobank

Andrea Califano's presentation